We have continued the characterization of autoantibodies to CD4 found in the serum of 15% of HIV positive individuals. These antibodies recognize epitopes dependent on the carboxy-terminus of soluble CD4 and are not exposed on membrane CD4 either on the cell surface or under denaturing western blotting conditions. In addition to the conformational carboxy terminal epitopes, peptide binding analysis has further identified linear epitopes within the CD4 fourth domain reactive with patient auto- antibodies. The data demonstrates that autoepitope exposure is a consequence of HIV envelope interaction with mCD4, which modifies the CD4 intracellular synthetic pathway leading to aberrant CD4 degradation. HIV- induced degradation appears to occur both in the endoplasmic reticulun and lysosomal intracellular compartments. Current experiments are directed at evaluating the role of the HIV VPU gene product and HIV protease in the mechanism of autoepitope exposure. HIV induced autoimmunity to CD4 provides a model system for defining molecular mechanisms of autoimmunity and for dissecting the role autoimmunity in AIDS pathogenesis.